It has been known that JAK3, as well as JAK1, JAK2 and TYK2, is a non-receptor tyrosine kinase belonging to a JAK family, and that JAK3 is involved in the signaling of various cytokines.
JAK1, JAK2 and TYK2 are expressed in a wide range of tissues, whereas the expression of JAK3 is mainly limited to lymphocytes such as T cells, B cells, and natural killer cells. JAK1- and JAK2-deficient mice are embryonic lethal, or die soon after the birth, whereas JAK3-deficient mice or humans develop severe combined immunodeficiency due to the lymphocyte dysfunction.
It is assumed that a JAK3 inhibitor inhibit the signals of six types of cytokines (i.e., IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), so as to specifically suppress the function of lymphocytes such as T cells or B cells, which play an important role in an immune system. Thus, it is anticipated that such a JAK3 inhibitor can be an effective therapeutic agent for diseases associated with activation of the aforementioned cells, having minimum expression of side effects (Non Patent Literatures 1 and 2).
It has been reported that examples of the disease, which can be treated with the JAK3 inhibitor, include autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis-dermatomyositis, Sjogren's syndrome, Behcet's disease, etc.), allergic disease (bronchial asthma, allergic rhinitis/hay fever, atopic dermatitis, food allergy, anaphylaxis, drug allergy, hives, conjunctivitis, etc.), nervous system disease (multiple sclerosis, Alzheimer's disease, etc.), inflammatory bowel disease (ulcerative colitis, Crohn's disease), psoriasis, contact dermatitis, diabetes, celiac disease, viral infectious disease, acute respiratory distress syndrome (ARDS), graft-versus-host disease (GVHD), transplant rejection, hematologic malignancy (lymphoma, leukemia), and other malignant tumors (Non Patent Literatures 3 to 8).
Moreover, Tofacitinib (Pfizer), a JAK3 inhibitor, has been used as a therapeutic agent for rheumatoid arthritis in clinical sites. It has been reported that this JAK3 inhibitor has low selectivity to JAK3, and thus that side effects (lipid rise, anemia, neutropenia, immunosuppression, etc.) are caused by inhibition of JAK1 and JAK2 (Non Patent Literature 9).
Furthermore, an azaindole derivative having a cyclic substituent at 4-position and an azaindole derivative having cyclic substituents at 3- and 5-positions have been reported as JAK inhibitors. However, these azaindole derivatives have low selectivity to JAK3, and the inhibitory activity thereof is not sufficient (Patent Literatures 1 and 2).